This intention relates generally to tricyclic compounds and also tricyclic compounds which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making such tricyclic compounds.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the consequence of HIV-1 or HIV-2 virus following its complex viral life cycle. The virion life cycle involves the virion attaching itself to the host human T-4 lymphocyte immune cell through the binding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
RNA polymerase transcribes the integrated viral DNA into viral mRNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. In most cases, without therapeutic intervention, HIV causes the host""s immune system to be debilitated, allowing opportunistic infections to set in. Without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the HIV life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treating AIDS. This transcription must occur for the virion to reproduce because the virion""s genes are encoded in RNA and the host cell transcribes only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxythymidinene (d4T), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-cytidine (3TC) have been shown to be relatively effective in certain cases in halting HIV replication at the reverse transcriptase (RT) stage.
An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs). As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.
U.S. Pat. No. 5,874,430 describes benzoxazinone non-nucleoside reverse transcriptase inhibitors for the treatment of HIV. U.S. Pat. No. 5,519,021 describe non-nucleoside reverse transcriptase inhibitors which are benzoxazinones of the formula: 
wherein X is a halogen, Z may be O.
EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula (A): 
wherein G is a variety of groups, R3 and R4 may be H, Z may be O, R2 may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R1 may be a variety of groups including substituted alkyl.
WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R3 and R4 may be H, Z may be O, R2 is substituted alkenyl or substituted alkynyl, and R1 is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(xe2x88x92)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.
Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al., Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al., J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al., J. Org. Chem. 1995, 60, 1590-1594.
DE 4,320,347 illustrates quinazolinones of the formula: 
wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a given inhibitor. Thus, there is an important need to develop additional inhibitors to further combat HIV infection.
Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, including a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide novel tricyclic compounds for use in therapy.
It is another object of the present invention to provide the use of novel tricyclic compounds for the manufacture of a medicament for the treatment of HIV infection.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
wherein R1, R2, R8, n, A, B, W, X, Y, and Z are defined below, including any stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

or a stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt form thereof, wherein:
n is selected from 0, 1, 2 and 3;
A is a ring selected from the group: 
wherein a ring nitrogen in ring A may optionally be in an N-oxide form;
said ring A being substituted with 0-3 B, said substituent B being independently selected from the group C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, xe2x80x94Sxe2x80x94C1-4alkyl, OCF3, CF3, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, and xe2x80x94NR5R5a;
W is N or CR3;
X is N or CR3a;
Y is N or CR3b;
Z is N or CR3c;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1 is selected from the group C1-3 alkyl substituted with 0-7 halogen, and cyclopropyl substituted with 0-5 halogen;
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OR2c, xe2x80x94OCHR2aR2b, xe2x80x94OCH2CHR2aR2b, xe2x80x94O(CH2)2CHR2aR2b, xe2x80x94OCHR2aC(R2a)xe2x95x90C(R2b)2, xe2x80x94OCHR2aC(R2a)xe2x95x90C(R2b)2, xe2x80x94OCHR2aCxe2x89xa1Cxe2x80x94R2b, xe2x80x94SR2c, xe2x80x94SCHR2aR2b, xe2x80x94SCH2CHR2aR2b, xe2x80x94S(CH2)2CHR2aR2b, xe2x80x94SCHR2aC(R2a)xe2x95x90C(R2b)2, xe2x80x94SCHR2aC(R2a)xe2x95x90(R2b)2, xe2x80x94SCHR2aCxe2x89xa1Cxe2x80x94R2b, xe2x80x94NR2aR2c, xe2x80x94NHCHR2aR2b, xe2x80x94NHCH2CHR2aR2b, xe2x80x94NH(CH2)2CHR2aR2b, xe2x80x94NHCHR2aC(R2a)xe2x95x90C(R2b)2, xe2x80x94NHCHR2aC(R2a)xe2x95x90(R2b)2, and xe2x80x94NHCHR2aCxe2x89xa1Cxe2x80x94R2b;
R2a is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R2b is H or R2c;
R2c is selected from the group methyl substituted with 0-3 R3f, C1-6 alkyl substituted with 0-3 R4, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, phenyl substituted with 0-2 R3d, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3d;
alternatively, the group xe2x80x94NR2aR2c represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms are replaced by O or NR5;
R3 is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, xe2x80x94SO2NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
R3a is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, xe2x80x94SO2NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3b is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
alternatively, R3a and R3b together form xe2x80x94OCH2Oxe2x80x94;
R3c is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
alternatively, R3b and R3c together form xe2x80x94OCH2Oxe2x80x94;
R3d, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
R3e, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
R3f, is selected from the group group H, F, Cl, Br, I, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94Oxe2x80x94C3-10 carbocycle substituted with 0-2 R3e, xe2x80x94O (CO) xe2x80x94R13, xe2x80x94OS (O)2C1-4alkyl, xe2x80x94NR12R12a, xe2x80x94C(O)R13, xe2x80x94NHC(O)R13, xe2x80x94NHSO2R10, and xe2x80x94SO2NR12R12a;
R4 is selected from the group H, F, Cl, Br, I, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94Oxe2x80x94C3-10 carbocycle substituted with 0-2 R3e, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a, C1-6 alkyl substituted with 0-2 R3e, C3-10 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-10 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3e;
R5 and R5a are independently selected from the group H and C1-4 alkyl;
alternatively, R5 and R5a, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-1 O or N atoms;
R6 is selected from the group H, OH, C1-4 alkyl, C1-4 alkoxy, and NR5R5a;
R7 is selected from the group H, C1-3 alkyl and C1-3 alkoxy;
R8 is selected from the group H, (C1-6 alkyl)carbonyl, C1-6 alkoxyalkyl, (C1-4 alkoxy)carbonyl, C6-10 aryloxyalkyl, (C6-10 aryl)oxycarbonyl, (C6-10 aryl)methylcarbonyl, (C1-4 alkyl)carbonyloxy(C1-4 alkoxy)carbonyl, C6-10 arylcarbonyloxy(C1-4 alkoxy)carbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C1-4 alkoxy)carbonyl, and (C1-6 alkyl substitued with NR5R5a)carbonyl; and
R10 is selected from the group C1-4 alkyl and phenyl
R11 is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with C3-6cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl;
R12 and R12a are independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
alternatively, R12 and R12a can join to form 4-7 membered ring; and
R13 is selected from the group H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94Oxe2x80x94C2-6 alkenyl, xe2x80x94Oxe2x80x94C2-6 alkynyl, NR12R12a, C3-6carbocycle, and xe2x80x94Oxe2x80x94C3-6carbocycle.
[2] In another embodiment, the present invention provides compounds of formula (I) as set forth above, wherein:
R1 is selected from the group C1-3 alkyl substituted with 1-7 halogen, and cyclopropyl;
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OR2c, xe2x80x94OCHR2aR2b, xe2x80x94OCH2CHR2aR2b, xe2x80x94O(CH2)2CHR2aR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2c, xe2x80x94OCHR2aCxe2x89xa1CR2b, xe2x80x94NR2aR2c, xe2x80x94SR2c, xe2x80x94SCHR2aR2b, xe2x80x94SCH2CHR2aR2b, xe2x80x94SCHR2aCHxe2x95x90CHR2b, xe2x80x94SCHR2aCHxe2x95x90CHR2c, and xe2x80x94SCHR2aCxe2x89xa1CR2b;
R2a is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R2b is H or R2c;
R2c is selected from the group methyl substituted with 0-3 R3f, C1-5 alkyl substituted with 0-3 R4, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, and phenyl substituted with 0-2 R3d;
R3 and R3a, at each occurrence, are independently selected from the group H, C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, NHC(O)NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3b and R3c, at each occurrence, are independently selected from the group H, C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3a and R3b together form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from the group H, Cl, F, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C3-5 carbocycle substituted with 0-2 R3e, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a, C1-4 alkyl substituted with 0-2 R3e, C3-5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3e;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; and
R7 is selected from the group CH3, C2H5, CH(CH3)2, OCH3, OC2H5, and OCH(CH3)2.
[3] In an alternative embodiment the present invention also provides compounds of formula (I) as described above, wherein:
ring A is selected from 
R1 is selected from the group CF3, C2F5, CHF2, CF2CH3 and cyclopropyl;
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OR2c, xe2x80x94OCHR2aR2b, xe2x80x94OCH2CHR2aR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2c, xe2x80x94OCHR2aCxe2x89xa1CR2b, and xe2x80x94NR2aR2c;
R2a is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R2b is H or R2c;
R2c is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 0-3 R4, C2-3 alkenyl substituted with 0-2 R4, C2-3 alkynyl substituted with 0-1 R4, and C3-6 cycloalkyl substituted with 0-2 R3d;
R3, R3a, R3b, and R3c, at each occurrence, are independently selected from the group H, C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3e, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, xe2x80x94NR5R5a, xe2x80x94C(O)R6, and xe2x80x94SO2NR5R5a;
R3f is selected from the group group H, F, Cl, Br, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94O-cyclopropyl substituted with 0-2 R3e, xe2x80x94O-cyclobutyl substituted with 0-2 R3e, xe2x80x94O-phenyl substituted with 0-2 R3e, xe2x80x94O(CO)xe2x80x94R13, xe2x80x94OS(O)2C1-4alkyl xe2x80x94NR12R12a, xe2x80x94C (O)R13, xe2x80x94NHC(O)R13, xe2x80x94NHSO2R10, and xe2x80x94SO2NR12R12a;
R4 is selected from the group H, Cl, F, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94C3-10 carbocycle substituted with 0-2 R3e, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a C1-4 alkyl substituted with 0-1 R3e, C3-5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; and
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5;
R11 is selected from methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, CF3, CH2CF3, CH2CH2CF3, xe2x80x94CH2-cyclopropyl, and cyclopropyl;
R12 and R12a are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, and cyclopropyl;
R13 is selected from the group H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, C1-6 haloalkyl, methoxy, ethoxy, propoxy, i-propoxy, butoxy, NR12R12a, cyclopropyl, cyclobutyl, cyclopropoxy, and cyclobutoxy.
[4] Another embodiment of the present invention include compounds of formula (I) as described above, wherein:
R1 is CF3, CF2CH3, or CHF2;
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OCH2R2b, xe2x80x94OCH2CH2R2b, xe2x80x94OCH2CHxe2x95x90CHR2b, xe2x80x94OCH2Cxe2x89xa1CR2b, and xe2x80x94NR2aR2c;
R2b is H or R2c;
R2c is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 0-3 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4;
R3, R3a, R3b, and R3c, at each occurrence, are independently selected from the group H, C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3e, at each occurrence, is independently selected from the group CH3, xe2x80x94OH, OCH3, OCF3, F, Cl, and xe2x80x94NR5R5a;
R3f, is selected from the group group H, F, Cl, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94O(CO)xe2x80x94R13, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a, and xe2x80x94NHC(O)NR12R12a;
R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; and
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5.
[5] Another embodiment of the present invention include compounds of formula (I) as described above, wherein:
n is 0 or 1;
ring A is optionally in an N-oxide form;
R1 is CF3, CHF2, or CF2CH3;
R2 is selected from the group xe2x80x94R2c, xe2x80x94OR2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OCH2R2b, xe2x80x94OCH2CH2R2b, xe2x80x94OCH2Cxe2x95x90Cxe2x80x94R2b, xe2x80x94OCH2Cxe2x89xa1Cxe2x80x94R2b, xe2x80x94NR2aR2c, xe2x80x94SR2c, xe2x80x94SCH2R2b, xe2x80x94SCH2CH2R2b, xe2x80x94SCH2CHxe2x95x90CHR2b,and xe2x80x94SCH2Cxe2x89xa1CR2b;
R2b is H or R2c;
R2c is selected from the group methyl substituted with 0-2 R3f, ethyl substituted with 0-3 R4, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4 ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R4, and cyclopropyl substituted with 0-1 R3d;
R3e, at each occurrence, is independently selected from the group CH3, xe2x80x94OH, OCH3, OCF3, F, Cl, and xe2x80x94NR5R5a;
R3f, is selected from the group group H, F, Cl, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94O(CO) xe2x80x94R13, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a, and xe2x80x94NHC (O)NR12R12a;
R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5; R8 is H.
[6] Another embodiment of the present invention include compounds of formula (I) as described above, wherein:
n is selected from 0 or 1;
A is selected from 
B is selected from methyl, ethyl, propyl, xe2x80x94OH, Cl, Br, xe2x80x94Sxe2x80x94CH3,
W is CR3;
X is CR3a;
Y is CR3a;
Z is N or CR3a;
R1 is selected from CF3, CHF2, and CF2CH3;
R2 is selected from xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OR2c, xe2x80x94OCH2Cxe2x95x90Cxe2x80x94R2b, xe2x80x94OCH2Cxe2x89xa1Cxe2x80x94R2b, and xe2x80x94NR2aR2c;
R2a is H;
R2b is H;
R2c is selected from the group methyl substituted with 0-3 R3f, ethyl substituted with 0-3 R4, propyl substituted with 0-3 R4, i-propyl substituted with 0-3 R4, butyl substituted with 0-3 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R4;
R3 is H;
R3a is H, F, Cl, or Br;
R3b is H;
R3c is H;
R3e, at each occurrence, is independently selected from the group H, methyl, and ethyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
R3f is selected from H, F, Cl, OH, xe2x80x94OR11, xe2x80x94OSO2methyl, xe2x80x94NR12R12a, and xe2x80x94NHC(O)NR5R5a;
R4 is selected from H, F, xe2x80x94OH, xe2x80x94Oxe2x80x94i-propyl, xe2x80x94OS(O)2CH3, cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl, N-morpholinyl, 2-pyridyl, 3-pyridyl, 4-pyridiyl, N2-methyl-N1-piperidinyl, N-piperidinyl, N-pyrrolidinyl, and N-piperazinyl;
R8 is H;
R11 is selected from H, methyl, ethyl, propyl, i-propyl, CH2cyclopropyl, and cyclopropyl; and
R12 and R12a are independently selected from H, methyl, ethyl, propyl, i-propyl, and cyclopropyl.
[7] Another embodiment of the present invention includes those compounds wherein the compound is of formula (Ic): 
[8] Another embodiment of the present invention includes those compounds wherein the compound is of formula (Id): 
Another embodiment of the present invention include compounds of formula (I) wherein:
ring A is selected from: 
ring A is optionally in an N-oxide form.
Another embodiment of the present invention include compounds of formula (I) wherein:
ring A is selected from: 
ring A is optionally in an N-oxide form.
In another embodiment, the present invention provides ring A is 
In another embodiment, the present invention provides ring A is 
In another embodiment, the present invention provides ring A is 
In another embodiment, the present invention provides the N on ring A is in the N-oxide form.
In another embodiment, the present invention provides the N on ring A is not in the N-oxide form.
Another embodiment of the present invention include compounds of formula (I) wherein:
W is CR3;
X is CR3a;
Y is CR3b; and
Z is CR3c.
Another embodiment of the present invention include compounds of formula (I) wherein:
W is CR3;
X is CR3a;
Y is CR3b; and
Z is selected from N and CR3c.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, OR2c, xe2x80x94OCHR2aR2b, xe2x80x94OCH2CHR2aR2b, xe2x80x94O (CH2)2CHR2aR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2c, xe2x80x94OCHR2aCxe2x89xa1CR2b, xe2x80x94NR2aR2c, xe2x80x94SR2c, xe2x80x94SCHR2aR2b, xe2x80x94SCH2CHR2aR2b, xe2x80x94SCHR2aCHxe2x95x90CHR2b, xe2x80x94SCHR2aCHxe2x95x90CHR2c, and xe2x80x94SCHR2aCxe2x89xa1CR2b.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2 is selected from the group xe2x80x94R2c, xe2x80x94OH, xe2x80x94CN, xe2x80x94OR2c, xe2x80x94OCHR2aR2b, xe2x80x94OCH2CHR2aR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2c, xe2x80x94OCHR2aCxe2x89xa1CR2b, and xe2x80x94NR2aR2c.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2 is selected from the group xe2x80x94R2c, xe2x80x94OR2c, xe2x80x94OCHR2aR2b, OCH2CHR2aR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2b, xe2x80x94OCHR2aCHxe2x95x90CHR2c, xe2x80x94OCHR2aCxe2x89xa1CR2b, and xe2x80x94NR2aR2c.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2c is selected from the group methyl substituted with 0-3 R3f, C1-5 alkyl substituted with 0-3 R4, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, and phenyl substituted with 0-2 R3d.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2c is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 0-3 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4.
Another embodiment of the present invention include compounds of formula (I) wherein:
R2c is selected from the group methyl substituted with 0-2 R3f, ethyl substituted with 0-3 R4, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R4, and cyclopropyl substituted with 0-1 R3d.
Another embodiment of the present invention include compounds of formula (I) wherein:
R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl.
Another embodiment of the present invention include compounds of formula (I) wherein:
R8 is H.
Another embodiment of the present invention include compounds of formula (I) wherein:
R4 is selected from H, F, xe2x80x94OH, xe2x80x94Oxe2x80x94i-propyl, xe2x80x94OS(O)2CH3, cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl, N-morpholinyl, 2-pyridyl, 3-pyridyl, 4-pyridiyl, N2-methyl-N1-piperidinyl, N-piperidinyl, N-pyrrolidinyl, and N-piperazinyl; and
[7] Compounds of the present invention include compounds of formula (I), or a stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt form thereof, or N-oxide forms thereof, wherein the compound of formula (I) is selected from:
the compounds of the Examples, Table 1, Table 2, Table 3, Table 4, and
7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(benzyloxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclobutylmethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(ethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8] naphthyridine,
7-Chloro-5-(hydroxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(n-propoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(i-propoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(butyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(methoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5(S)-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5(R)-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(2-cyclopropylethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(2,2,2-trifluoroethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(propargoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(ethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclopropylmethoxy)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(n-butyl)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(2-cyclopropylethyl)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-2-(methylthio)-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(i-butoxy)-5,10-dihydro-2-(methylthio)-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(benzyloxy)-5,10-dihydro-2-(methylthio)-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(2-pyridylmethoxy)-5,10-dihydro-2-(methylthio)-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(cyclopropylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(i-propylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(N,N-dimethylaminoethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(N-morpholinylethylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-((1-methylcyclopropyl)methoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(3,3,3-trifluoroprop-1-oxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclopropylmethylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(methylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(ethylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
(S)-7-Chloro-5-(cyclopropylethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
(R)-7-Chloro-5-(cyclopropylethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Fluoro-5-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Fluoro-5-(cyclopropylethoxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Fluoro-5-(allyloxy)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(phenylamino)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclopropylmethoxy)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(n-butyl)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclopropylethyl)-2-methyl-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine,
7-Chloro-5-(cyclobutylmethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(methoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
(S)-7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
(R)-7-Chloro-5-(cyclopropylmethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(N-piperidinylethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(N-pyrrolidinylethoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-((4-methylpiperazin-1-yl)prop-1-oxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(prop-1-oxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(N,N-dimethylaminoprop-1-yl)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(benzyloxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(3-pyridinylmethyl)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(allyloxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline,
7-Chloro-5-(propargoxy)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline, and
7-Chloro-5-(N,N-dimethylaminoethyl)-5,10-dihydro-5-(trifluoromethyl)pyrimido[4,5-b]quinoline;
7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Allyloxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine-5-carbonitrile;
7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-ol;
5-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-prop-2-ynyloxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-(1-methyl-cyclopropylmethoxy)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-(2-cyclopropyl-ethoxy)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-isopropyl-amine;
(7-Chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-cyclobutylmethyl-amine;
7-Chloro-5-(2-cyclopropyl-ethyl)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Cyclobutylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Fluoro-1-oxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-isopropyl-amine;
5-Cyclobutylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-2-ol;
7-Chloro-5-(pyridin-2-ylmethoxy)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
5-Butyl-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Chloro-1-oxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-ol;
7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Fluoro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
5-Cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-pyridin-2-ylmethyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
3,7-Dichloro-5-pentyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
3,7-Dichloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-(2-Cyclopropyl-ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
3-Chloro-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
3-Chloro-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Butyl-7-chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(S) 3-Chloro-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-methanol;
7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Fluoro-5-isopropoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
Methanesulfonic acid 7-chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-ylmethyl ester;
7-Chloro-5-isopropoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-acetonitrile;
7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine-5-carbaldehyde;
3-Bromo-5-cyclopropylmethoxy-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Butyl-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Diisopropoxymethyl-7-fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Fluoro-5-isopropoxymethyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-isobutyl-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-propoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(S) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(R) 7-Fluoro-5-isobutoxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-acetaldehyde;
7-Chloro-5-(2,2-diisopropoxy-ethyl)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
2-(7-Chloro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-ethanol;
7-Chloro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(R) 7-Fluoro-5-(2-isopropoxy-ethyl)-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-acetic acid tert-butyl ester;
(7-Fluoro-1-oxy-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-acetic acid tert-butyl ester;
(7-Fluoro-5-trifluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridin-5-yl)-acetic acid;
7-Chloro-5-cyclopropylmethoxy-2-methylsulfanyl-5-trifluoromethyl-5,10-dihydro-pyrimido[4,5-b]quinoline;
7-Chloro-5-isobutoxy-2-methylsulfanyl-5-trifluoromethyl-5,10-dihydro-pyrimido[4,5-b]quinoline;
5-Benzyloxy-7-chloro-2-methylsulfanyl-5-trifluoromethyl-5,10-dihydro-pyrimido[4,5-b]quinoline;
7-Chloro-2-methylsulfanyl-5-(pyridin-2-ylmethoxy)-5-trifluoromethyl-5,10-dihydro-pyrimido[4,5-b]quinoline;
7-Chloro-5-cyclopropylmethoxy-5-trifluoromethyl-5,10-dihydro-pyrimido[4,5-b]quinoline 1-oxide;
7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
5-Cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-7-fluoro-5,10-dihydro-benzo[b][1,8]naphthyridine;
5-Cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-7-fluoro-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-Chloro-5-(1,1-difluoro-ethyl)-5-isobutoxy-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Chloro-5-(1,1-difluoro-ethyl)-5-isobutoxy-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(R) 7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
(S) 7-Chloro-5-cyclopropylmethoxy-5-(1,1-difluoro-ethyl)-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10-dihydro-1,8,9-triaza-anthracene;
3-Chloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10-dihydro-1,8,9-triaza-anthracene 8-oxide;
3,6-Dichloro-10-cyclopropylmethoxy-10-trifluoromethyl-9,10-dihydro-1,8,9-triaza-anthracene;
3-Chloro-10-isobutoxy-10-trifluoromethyl-9,10-dihydro-1,8,9-triaza-anthracene;
3-Chloro-10-isobutoxy-10-trifluoromethyl-9,10-dihydro-1,8,9-triaza-anthracene 8-oxide;
7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10-dihydro-benzo[b][1,8]naphthyridine;
7-Chloro-5-difluoromethyl-5-isopropoxymethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide;
7-chloro-1,5-dihydro-5-(N-ethylaminomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
7-chloro-5,10-dihydro-5-(N-isopropylaminomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
7-chloro-5,10-dihydro-5-(N-isopropyl-N-ethylaminomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
7-chloro-5-(N,N-diethylaminomethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
5-(acetamidomethyl)-7-chloro-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
5,10-dihydro-7-fluoro-5-(N-methylsulfonylmethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
5,10-dihydro-7-fluoro-5-(isopropylamidomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine;
5,10-dihydro-7-fluoro-5-(isopropylguanadinomethyl)-5-(trifluormethyl)benzo[b][1,8]napthyridine;
1,5-dihydro-7-fluoro-5-(N-isopropylmethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide);
5-(N,N-diethylaminomethyl)-5,10-dihydro-7-fluoro-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide);
5,10-dihydro-5-(N,N-dimethylaminomethyl)-7-fluoro-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide);
7-chloro-5,10-dihydro-5-(N-isopropylaminomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide);
7-chloro-5-(N,N-diethylaminomethyl)-5,10-dihydro-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide); and
7-chloro-5,10-dihydro-5-(N,N-dimethylaminomethyl)-5-(trifluoromethyl)benzo[b][1,8]napthyridine-1-(N-oxide.
Another embodiment of the present invention are those compounds wherein the heterocyclic ring A is in an N-oxide form.
The present invention also provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof
The compositions and methods of use comprising the compounds of the present invention include compositions and methods of use comprising the compounds of the present invention and stereoisomeric forms thereof, mixtures of stereoisomeric forms thereof, complexes thereof, crystalline forms thereof, prodrug forms thereof and pharmaceutically acceptable salt forms thereof
In another embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof
In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula (I); and
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
Preferred reverse transcriptase inhibitors useful in the above method of treating HIV infection are selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, HBY1293, GW867, ACT, UC-781, UC-782, RD4-2025, MEN 10979, and AG1549 (S1153). Preferred protease inhibitors useful in the above method of treating HIV infection are selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.
In another embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
In another embodiment, the reverse transcriptase inhibitor is AZT.
In another embodiment, the protease inhibitor is indinavir.
In another embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula (I); and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In another embodiment, the present invention provides novel tricyclic compounds for use in therapy.
In another embodiment, the present invention provides the use of novel tricyclic compounds for the manufacture of a medicament for the treatment of HIV infection.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The present invention is intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
As used herein, the following terms and expressions have the indicated meanings.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. By way of illustration, the term xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9cC1-C10 alkylxe2x80x9d is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. xe2x80x9cC1-4 alkylxe2x80x9d is intended to include C1, C2, C3, and C4 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. C2-10 alkenyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. C2-10 alkynyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. An oxo group may be a substituent on a nitrogen heteroatom to form an N-oxide. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, 5,10-dihydro-benzo[b][1,8]naphthyridinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrimido[4,5-b]quinolinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), HBY1293 (Hoechst), GW867 (Glaxo Wellcome), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), MEN 10979 (Menarini Farmaceutici) and AG1549 (S1153; Agouron).
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Examples of prodrugs at R8 are C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention alone or in combination with other active ingredients or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. In the Schemes which follow, R1 is shown as a CF3 group, but could be any one of the presently described R1 groups. 
Scheme 1 illustrates the reaction between an aryl/heterocyclic amine with 2-chloronicotinic acid to obtain the di-substituted amine A which can be cyclized using PPA to give B. Protection of the amine, followed by reaction with TMSCF3 in the presence of TBAF gives D, which can be alkylated using a base and an alkylhalide and then deprotected to give F. 
Scheme 2 illustrates the aromatization of either D or F to give the compound G. The compound G can then be alkylated either through reaction with a Grignard reagent, or alternatively, by reaction with an organometalic reagent to give H. 
When required, separation of the diasteriomeric material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of formula (I) may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.